tbuckley/cabot-search huggingface dataset:
Prospective characterization of oral and gut microbiome in a high-risk pancreatic cancer cohort.
Authors: Seyda Baydogan, Chirayu Mohindroo, Maria Fernanda Montiel, Joseph Petrosino, Anirban Maitra, Michael Paul Kim, Manoop S. Bhutani, James R White, Florencia McAllister
Journal: Journal of Clinical Oncology (2023)

691 Background: Pancreatic cancer (PC) is the third leading cause of cancer death in the United States. The high mortality associated with PC is attributed to multiple reasons: lack of effective therapies, aggressive biology and late diagnosis. Due to the absence of reliable early disease biomarkers, PC screening is largely dependent on imaging. Recent studies have highlighted the importance of the gut and tumor microbiome in PC. We present here the first report of oral and gut microbiome prospective analysis of PC high-risk individuals (PC-HRI) undergoing screening. Methods: We collected periodontal and stool samples at the University of Texas MD Anderson Cancer Center from 2017-2022. A total of 448 samples, consisting of 250 oral and 198 gut samples were obtained. Samples were collected from PC (n=73), PC-HRI (n=34), and healthy (n=143) individuals. 16s rRNA sequencing was used to characterize the oral and gut microbiome and statistical analysis and correlation with imaging and clinical characteristics were performed. Results: We identified three phyla, namely Proteobacteria, Actinobacteria, and Fusobacteria as significantly more abundant in the gut microbiome of PC patients. Conversely, Proteobacteria was decreased in the oral microbiome of PC patients. At the class level, Gammaproteobacteria (GP) oral/gut ratio was significantly decreased in PC patients compared with healthy individuals (p=0.02). Analysis of PC-HRI revealed also low GP oral/gut ratio in high-risk individuals who were diagnosed with worrisome pancreatic focal lesions. Interestingly, Gammaproteobacteria (GP) is one of the main classes of bacteria detected in pancreatic cancer tissue. GP shifts in oral and gut environments could be implicated in pancreatic early tumorigenesis and serve as biomarker of the disease. Additionally, gut bacteria with metabolic pathways related to lipid metabolism were more enriched in PC patients and PC-HRI with focal lesions compared to healthy controls. Conclusions: Gammaproteobacteria oral/gut ratio represents a potential novel biomarker which could predict presence of early high risk-pancreatic focal lesions in PC-HRI. Taken together, this report provides observational evidence about changes in oral and gut microbiome in patients with pancreatic cancer but even more importantly, the fact that those changes could be detected in PC-HRI with early high-risk lesions. Broader validation in other high-risk cohorts would be required. Detection of GP oral/gut ratio would represent an inexpensive, non-invasive method that could be useful for PC screening. Functional studies should be performed to determine how GP shifts can contribute with pancreatic tumorigenesis. Research supported by CPRIT (Grant Number: RP200173) and philanthropic funding through the MD Anderson Moonshot Program.
Intertumor heterogeneity of locally advanced gastric cancer.
Authors: Natalia P. Belyak, Svetlana Kutukova, Rashida Orlova, Ekaterina Kaledina, Alexandra Androsova, Natalia V. Zhukova
Journal: Journal of Clinical Oncology (2023)

435 Background: The aim of the present study was to determine to the effect of HER2, dMMR, PD-L1 status in the primary tumor and in metastasis to the regional lymph node of GC patients. Methods: A total of 44 patients with primary loco-regional (N+) gastric adenocarcinoma were recruited, and two formalin-fixed paraffin-embedded (FFPE) tumor-containing blocks of each patient (one block with primary tumor and one block with metastasis to the regional lymph node)were selected for HER2, dMMR, PD-L1 (CPS) immunohistochemical (IHC) assay. Clinicopathological characteristics were recorded, and intertumoral heterogeneity of HER2, dMMR, PD-L1 IHC expression was determined. Results: The study included 19 women and 25 men, 30 patients had Laurén’s intestinal type of cancer, 14 had a Laurén’s diffuse type. In 5 patients (11.4%) overexpression of Her-2 neu was detected, and heterogeneity was detected in all five cases: in three patients with HER2 overexpression in the primary tumor, no overexpression was detected in the metastasis to the regional lymph node, in two cases overexpression was detected in the metastasis, while no overexpression was observed in the primary tumor. 2 patients showed signs of dMMR (4.5%), in one case, heterogeneity in dMMR status was also revealed: signs of dMMR in the primary tumor and its absence in regional metastasis (pMMR). Assessment of PD-L1 status was carried out using the CPS formula. Ten patients (22.7%) had a negative PD-L1 status (CPS=0) both in the primary tumor and in regional metastasis. Positive PD-L1 status in the primary tumor: in 24 patients CPS= 0-5 (54.5%), in 5 patients CPS= 5-10 (11.4%) and 5 patients CPS= 10 or more (11.4% ). Positive PD-L1 status in regional lymph node metastasis: in 24 patients CPS= 0-5 (54.5%), in 5 patients CPS= 5-10 (11.4%) and in 5 patients CPS= 10 or more ( 11.4%). In 5 cases (11.4%) marked heterogeneity in PD-L1 status between the primary tumor and its regional metastasis (1 case with dMMR heterogeneity). Conclusions: The research findings in this paper indicate that the intertumoral heterogeneity of HER2 overexpression is common in GC patients, We highly recommend multi-block HER2 assessment for accurate diagnosis of GC. Given the rarity of status detection dMMR, a study in a larger number of patients is required, however, our data also confirm the presence of heterogeneity in dMMR status, and probably the possibility of metastasis of a more aggressive pMMR clone. Heterogeneity in PD-L1 status is quite rare and amounted to only 11.4%, which also has important practical significance.
Guideline compliance and outcomes of genetic testing in pancreatic cancer patients.
Authors: Derk C.F. Klatte, Heather D. Hardway, Jason S. Starr, Douglas L. Riegert-Johnson, Kristin E. Clift, Thomas P. Potjer, Monique E. van Leerdam, R. John Presutti, Michael B. Wallace, Yan Bi
Journal: Journal of Clinical Oncology (2023)

688 Background: Guidelines recommend patients with pancreatic ductal adenocarcinoma (PDAC) undergo genetic testing for germline pathogenic variants (PV). The aim of this study was to evaluate compliance with recently updated guidelines (May 2019) and assess subsequent uptake and outcomes of genetic testing in PDAC patients. In addition, social and clinical factors associated with genetic testing were assessed. Methods: A retrospective chart review of patients diagnosed with PDAC between May 2018 and August 2020 was performed. Discussion and subsequent uptake of genetic testing was reviewed and compared between a 12-month period before (pre-guideline) and a 12-month period after (post-guideline) guidelines were updated, accounting for a three-month transition period. Univariate and multivariate logistic regression analysis was used to assess factors predictive of undergoing genetic testing. Results: In total, 534 patients with PDAC were identified; 321 (60.1%) in the pre-guideline period and 213 (39.9%) in the post-guideline period. The mean age at diagnosis was 68 years and 47% were female. Genetic testing was discussed in 34% (109/321) of pre-guideline and in 39% (84/213) of post-guideline patients ( P = .23). Of those, 82% (89/109) of patients in pre-guideline and 75% (63/84) in post-guideline groups underwent subsequent genetic testing ( P = .71). In 26 (17.1%) of 152 tested patients, a PV was identified, of which 17 (11.2%; 17/152) had a PDAC-associated PV. Age, cancer stage at diagnosis, length of survival, and having a first-degree relative with pancreatic cancer were significant predictors of genetic testing on multivariate analysis. Conclusions: Adherence to recently updated guidelines is poor and germline genetic testing in PDAC patients remains insufficient. Efforts to increase awareness of benefits of testing, which include personalized therapies for patients and cascade testing in family members for subsequent enrollment in pancreatic cancer surveillance programs, could improve future uptake.[Table: see text]
IMbrave151: A phase 2, randomized, double-blind, placebo-controlled study of atezolizumab with or without bevacizumab in combination with cisplatin plus gemcitabine in patients with untreated, advanced biliary tract cancer.
Authors: Anthony B. El-Khoueiry, Zhenggang Ren, Hongjae Chon, Joon Oh Park, Jin Won Kim, Tiziana Pressiani, Daneng Li, Lyudmila Zhukova, Ming-Huang Chen, Stephen Paul Hack, Stephanie Wu, Bo Liu, Yulei Wang, Teresa Macarulla
Journal: Journal of Clinical Oncology (2023)

491 Background: VEGF blockade coupled with cytotoxic chemotherapy can promote an immune-permissive tumor microenvironment that can augment response to PD-L1 inhibition. IMbrave151 (NCT04677504) is a randomized, double-blind, global Phase II study evaluating the efficacy of atezolizumab (atezo), bevacizumab (bev) and cisplatin and gemcitabine (CisGem) as first-line treatment for patients with advanced biliary tract cancer (aBTC). Methods: Patients with previously untreated aBTC were randomized 1:1 to receive atezo (1200 mg every 3 weeks [q3w]) + bev (15 mg/kg q3w) or placebo + CisGem (cisplatin 25 mg/m 2 and gemcitabine 1000 mg/m 2 on Days 1 and 8 q3w) for up to 8 cycles, followed by atezo (1200 mg q3w) + bev (15 mg/kg q3w) or placebo until disease progression or unacceptable toxicity. Patients were stratified by disease status, geographic region and primary tumor location. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR), disease control rate and safety. No formal hypothesis testing was performed. Results: In total, 162 patients were randomized to receive either atezo + bev + CisGem (n=79) or atezo + placebo + CisGem (n=83). Median age 63 years, Asia/Rest of World (43/57%), ECOG PS 0/1 (53/48%), intrahepatic/extrahepatic cholangiocarcinoma and gallbladder (54/19/27%), and metastatic/locally advanced stage (82/18%). The HR for PFS was 0.76 (95% CI: 0.51, 1.14). Median PFS was 8.4 months for atezo + bev + CisGem and 7.9 months for atezo + placebo + CisGem; the 6-month PFS rates were 78% and 63%, respectively. The confirmed ORR was 24% for atezo + bev + CisGem and 25% for atezo + placebo + CisGem. DOR ≥6 months was 89% for atezo + bev + CisGem vs 47% for atezo + placebo + CisGem. The incidence of Grade 3 or 4 adverse events was 73% and 74% with atezo + bev + CisGem and atezo + placebo + CisGem, respectively. Median OS is not reached. Conclusions: Both combinations of IMbrave151 showed a manageable safety profile. The aggregate of data suggests that combining atezo with bev and chemotherapy may provide clinical benefit in a subset of patients with aBTC. Follow-up is ongoing for OS. Clinical trial information: NCT04677504 .
Impact of patient characteristics and treatment patterns on outcomes in potentially resectable pancreatic cancer (PC).
Authors: Andrew Steinmetz, Sameer H. Patel, Gregory C. Wilson, Jeffrey J. Sussman, Olugbenga Olanrele Olowokure, Jordan Kharofa, Syed A. Ahmad, Davendra Sohal
Journal: Journal of Clinical Oncology (2023)

681 Background: Treatment of PC remains a challenge, with surgery being the mainstay of potentially curative therapy. Even after surgical resection, however, many patients experience recurrence. There has been a shift toward treating PC as a systemic disease from diagnosis with neoadjuvant chemotherapy (nCT) or chemoradiation (nCRT). This study examines characteristics of real-world patients who were deemed to have resectable (R) or borderline resectable (BR) disease, and how they relate to overall survival (OS). Methods: This is a retrospective analysis of patients in an academic health system who presented for initiation of treatment for PC staged as R or BR. Descriptive data on patient characteristics, performance status (PS), laboratory values, neoadjuvant therapies, recurrence, and mortality were obtained. OS was evaluated using Kaplan-Meier analysis and log-rank tests. Two-sided p-values were calculated. Results: From electronic records at the University of Cincinnati, 129 patients were identified. Median age was 66 with baseline ECOG PS of mostly 0 (86, 67%) or 1 (40, 31%). Primary tumor site was most commonly head of pancreas (104, 81%). Of 129, 55 (43%) patients received surgery upfront; the rest received neoadjuvant therapy (39 nCRT, 35 nCT) with gemcitabine (68%) or 5-fluorouracil (32%) containing regimens. Of those receiving nCRT/nCT, 36 (49%) went on to resection; the rest experienced progression (27, 36%) or toxicities (11, 15%) including death. Of 129, 92 (71%) have died, with median OS of 20.1 months (95% CI 16.4 - 25.0) for the full cohort. On adjusted multivariable analysis, the following were associated with worse OS: failure to undergo resection (HR 5.65, 95% CI 3.17 - 10.09, p&lt;0.0001); receiving &lt;3 cycles nCT (HR 3.00, 95% CI 1.38 - 6.53, p=0.006); baseline CA 19-9 &gt;100 (HR 2.73, 95% CI 1.52 - 4.90, p=0.001); BR disease (HR 2.20, 95% CI 1.27 – 3.81, p=0.005); not receiving RT (HR 1.91, 95% CI 1.04 - 3.53, p=0.038). Regimen choice was not associated with OS. Conclusions: In this real-world PC dataset, surgical resection remains the mainstay of curative therapy. Inadequate nCRT/nCT lead to suboptimal outcomes, likely reflecting patient physiology and disease biology effects. Future trials should focus on maximizing neoadjuvant therapy with the goal of resection.[Table: see text]
Genetic heterogeneity of intrahepatic cholangiocarcinoma: Implications for outcome.
Authors: Yi Song, Thomas Boerner, Esther N. Drill, Paul Shin, Andrea Cercek, Nancy E. Kemeny, Ghassan K. Abou-Alfa, Christine A Iacobuzio-Donahue, Nikolaus Schultz, Henry S. Walch, Carlie S. Sigel, T. Peter Kingham, Kevin Soares, Alice Chia-chi Wei, Michael Ian D'Angelica, Jeffrey A. Drebin, Rohit Chandwani, James J. Harding, William R. Jarnagin
Journal: Journal of Clinical Oncology (2023)

595 Background: Intrahepatic cholangiocarcinoma (IHC) is characterized by marked clinical heterogeneity, likely the result of multiple cells of origin and variable driver gene alterations. The hidden-genome classifier is a statistical algorithm that classifies tumors by integrating multi-level genomic features. In this study, we trained the hidden-genome classifier with extrahepatic cholangiocarcinoma (EHC), gallbladder cancer (GBC) and hepatocellular carcinoma (HCC) as extremes of a spectrum to quantify the genetic heterogeneity of IHC with a view toward improved tumor classification. Methods: An IRB approved retrospective review of patients with biopsy confirmed IHC, EHC, GBC and HCC was conducted. All tumors were subjected to MSK-IMPACT to determine the mutational profile. A two-class model was built and internally validated with the genomic data of EHC/GBC as one class and HCC as the other class. IHC tumors were analyzed in the model and classified into three groups based on their proportional genetic resemblance to EHC/GBC (Biliary Class) or HCC (HCC Class), with the remainder as Intermediate Class. The classification thresholds were 90% resemblance to EHC/GBC or HCC and were determined by the inflection point of predicted survival. The survivals of the three groups were analyzed and compared. Results: A total of 1497 patients were included: IHC (733), EHC (208), GBC (258) and HCC (298). 527 IHC tumors with complete metagenetic information were analyzed in the model, showing a continuous spectrum of alterations, ranging from Biliary Class (122 tumors), Intermediate Class (375 tumors) to HCC Class (30 tumor). The biliary-class IHC was characterized by frequent alterations of IDH1 R132C, KRAS, SMAD4, ERBB2 gain, MDM2 gain, and CKDN2A loss, while the HCC-class IHC was primarily characterized by TERT alterations. In patients with unresected IHCs, the median survival ranged from 1 year (CI 0.77, 1.5) in Biliary Class, 1.8 years (CI 1.5, 2.0) in Intermediate Class, to 2 years (CI 0.93, NR) in HCC Class. In patients subjected to resection, the median survival of Biliary Class (2.4 years, CI 2.1, NR) was lower than both the Intermediate Class (5.1 years, CI 4.8, 6.9) and the HCC Class (3.4 years, CI 2.7, NR). Conclusions: By integrating multi-level genomic features, we leveraged the mutational heterogeneity to classify IHC based on its resemblance to EHC/GBC or HCC tumors. We found that the survival in IHC patients appeared to decline with increasing genomic similarity to Biliary Class. The results support a genomic basis for IHC’s variable clinical behavior and point to a role of mutational testing to guide clinical intervention. [Table: see text]
Adjuvant nab-paclitaxel plus S-1 versus oxaliplatin plus capecitabine after curative D2 gastrectomy in patients with stage III gastric adenocarcinoma: a phase 3 open-label, randomized controlled trial
Authors: Yu Pengfei, Yian Du, Zhiyuan Xu, Litao Yang, Jieer Ying, Ping Chen, Yunhai Wei, Yingjie Wu, Zhilong Yan, Hongtao Xu, Xiaojing Zhang, Yong Li, Zhichao Zheng, Zhiheng Chen, Xiangdong Cheng
Journal: Journal of Clinical Oncology (2023)

386 Background: Although adjuvant chemotherapy improvs the survival rate of stage III gastric cancer after curative D2 gastrectomy, the overall benefit is unsatisfactory. Therefore, the study was designed to evaluate the efficacy and safety of adjuvant nab-paclitaxel plus S-1 (AS) versus oxaliplatin plus capecitabine (CAPOX) in the treatment of stage III gastric adenocarcinoma (GAC) after curative D2 gastrectomy. Methods: This phase 3, open-label, randomized study was conducted in patients with stage III GAC after curative D2 gastrectomy. Patients were randomized (1:1) to receive adjuvant AS (100 mg/m 2 nab-paclitaxel on days 1 and 8; 40-60 mg oral S-1 twice daily on days 1-14) or CAPOX (130 mg/m 2 oxaliplatin on day 1; 1000 mg/m 2 oral capecitabine twice daily on days 1-14), repeat every 3 weeks for 8 cycles. The primary endpoint was the 3-year disease-free survival (DFS) rate by intention-to-treat analysis. Secondary endpoints included overall survival (OS) and safety. Results: Between March 2020 and August 2022, 280 patients were screened and 233 were randomly assigned to study treatment (AS, 115; CAPOX, 118). The median age was 62 years (range, 27-77) in AS and 63 years (range, 35-75) in CAPOX. The pathological stages were 42.61% stage IIIA, 34.78% stage IIIB, and 22.61% stage IIIC in AS, while those of CAPOX were 47.46% stage IIIA, 30.51% stage IIIB, and 22.03% stage IIIC. The 1-year DFS rate was 89.0% in AS versus 76.9% in CAPOX. The 1-year OS rate was higher in AS versus CAPOX (100% vs. 95.5%). Seven (6.09%) in AS and 11 (9.32%) in CAPOX experienced recurrence during follow-up; thereinto, one in CAPOX confirmed recurrence with tumor markers and clinical manifestations. Recurrence sites in AS and CAPOX involved the peritoneum (1 vs. 4), locoregional (1 vs. 2), and distant (5 vs. 6), of which, certain patients had 2 simultaneously. Among 6 deaths in CAPOX, 3 died from GAC, 1 died from other diseases and 2 died from unknown. The median relative dose intensity was 96.91% for nab-paclitaxel and 88.00% for S-1 in AS, 82.77% for oxaliplatin and 79.36% for capecitabine in CAPOX. Certain patients in AS (38.26%) and CAPOX (22.03%) experienced grade 3/4 adverse events (AEs). The most common AEs in AS and CAPOX included anemia (20.96% vs. 19.63%), neutropenia (30.70% vs. 21.02%), and thrombocytopenia (1.10% vs. 15.47%). Conclusions: In this study, AS showed longer trends in the DFS rate, OS rate, and manageable safety profile in patients with stage III GAC after curative D2 gastrectomy compared with CAPOX, suggesting a potential therapeutic option for this population. Clinical trial information: NCT04135781 .
Association of transanal minimally invasive surgical approach with oncologic outcomes over conventional transanal excision for early-stage rectal cancer: An analysis of the US Rectal Cancer Consortium.
Authors: Emilie Warren, Adriana C. Gamboa, Caroline Medin, Samantha Hendren, Scott E. Regenbogen, Jennifer Holder-Murray, Matthew Kalady, Aslam Ejaz, Alexander Hawkins, Paul Wise, Matthew Silviera, Shishir K. Maithel, Glen C. Balch
Journal: Journal of Clinical Oncology (2023)

145 Background: For early-stage rectal cancer, minimally invasive surgical (MIS) approaches such as transanal endoscopic microsurgery (TEM) and transanal minimally invasive surgery (TAMIS) have not been widely adopted over conventional transanal excision (TAE). Direct comparisons are lacking. Our aim was to compare oncologic and perioperative outcomes between the two approaches. Methods: We identified patients with Tis or T1 tumors who underwent TAE or MIS (TEM or TAMIS) between 2007-2017 from the US Rectal Cancer Consortium database. Patients who received neoadjuvant therapy were excluded. Primary outcomes were rate of recurrence and recurrence-free survival (RFS). Results: Of 1881 patients, 89 met inclusion criteria: 44 TAE and 45 MIS (20 TEM, 25 TAMIS). Median age was similar between groups (63.5 years TAE vs 61 years MIS; p=0.582). Patients in each group had similar functional status and tumor size (1.86 cm TAE vs 1.79 cm MIS, p=0.837). The majority of patients had tumors ≤ 6 cm from the anal verge (75.7% TAE vs 65.5% MIS, p=0.544). The TAE group had a 10.3% margin positive rate versus 0% in the MIS group (p=0.049). There was a lower incidence of recurrence in the MIS group (4.5%) compared to TAE (26%, p=0.01); all recurred locally except for one in the TAE group. Median follow-up time was 23.7 months. On Kaplan-Meier analysis, MIS approach was associated with improved 5-year RFS (86.4%, p=0.005) and local RFS (86.4%, p=0.01), versus TAE (46.9% and 50.5%, respectively). On univariate cox regression analysis, lymphovascular invasion was associated with worse RFS (HR 4.23, p=0.033) and local RFS (HR 5.26, p=0.02), while MIS approach was associated with improved RFS (HR 0.15, p=0.015) and local RFS (HR 0.17, p=0.023). On multivariable cox regression, only MIS approach remained associated with improved RFS (HR 0.09, p=0.028) and local RFS (HR 0.11, p=0.045). Perioperative complication and readmission rates were equal between the two groups. Conclusions: In patients with Tis and T1 rectal cancers who undergo local excision, an MIS approach (TEM or TAMIS) is associated with a decreased rate of recurrence and improved RFS and local RFS compared to TAE, with no significant difference in perioperative complication rate. The MIS approach should be more frequently incorporated into standard practice. [Table: see text]